N-phenyl-2-pyrimidine-amine derivatives

ABSTRACT

The present invention relates to novel amides and a process for preparing these amides.

This application is a divisional of U.S. application Ser. No.10/503,538, filed Jan. 20, 2005, which is a 371 of InternationalApplication No. PCT/EP03/01188, filed Feb. 6, 2003.

The present invention provides novel amides, a process for preparingthese amides and the use of these amides.

In particular, the present invention provides novel amides of formula I

wherein

one of the radicals R₁, R₂, R₃, R₄ and R₅ is

-   a) a radical selected from the group consisting of lower alkyl,    amino; mono- or di-lower alkylamino; lower alkanoylamino; lower    alkoxy-carbonyl; and lower alkyl which is substituted by amino,    mono- or di-lower alkylamino or lower alkanoylamino, or-   b) an unsubstituted or substituted radical selected from the group    consisting of benzylamino; benzoylamino; pyrrolidinyl; piperidyl;    piperazinyl; piperazinyl-carbonyl; morpholinyl, thiomorpholinyl; and    lower alkyl substituted by benzylamino, benzoylamino, halogene,    pyrrolidinyl, piperidyl, piperazinyl, e.g. 4-methyl-piperazinyl-,    thiomorpholinyl, or morpholinyl, the substituents of said    substituted radical being selected from the group consisting of    cyano; lower alkyl; hydroxy- or amino-substituted lower alkyl;    trifluoromethyl; free, etherified or esterified hydroxy; lower    alkoxy; lower alkanoyloxy; free, alkylated or acylated amino; mono-    or di-lower alkylamino; lower alkanoylamino; benzoylamino; free or    esterified carboxy; lower alkoxycarbonyl and halogen, and    and the other four radicals are independently hydrogen, cyano; lower    alkyl; hydroxy- or amino-substituted lower alkyl; trifluoromethyl;    free, etherified or esterified hydroxy; lower alkoxy; lower    alkanoyloxy; free, alkylated or acylated amino; mono- or di-lower    alkylamino; lower alkanoylamino; benzoylamino; free or esterified    carboxy; lower alkoxycarbonyl and halogen;    or

R₁ and R₂, R₂ and R₃, R₃ and R₄, or R₄ and R₅ together are a substitutedor unsubstituted alkylene radical having 4 carbon atoms, thesubstituents preferably being selected from cyano, unsubstituted orhydroxy-, amino- or 4-methyl-piperazinyl-substituted lower alkyl, suchas especially methyl, trifluoromethyl, free, etherified or esterifiedhydroxy, free, alkylated or acylated amino and free or esterifiedcarboxy;

and the other three radicals are independently hydrogen, cyano; loweralkyl; hydroxy- or amino-substituted lower alkyl; trifluoromethyl; free,etherified or esterified hydroxy; lower alkoxy; lower alkanoyloxy; free,alkylated or acylated amino; mono- or di-lower alkylamino; loweralkanoylamino; benzoylamino; free or esterified carboxy; loweralkoxycarbonyl and halogen;

and one of the radicals R₆, R₇ and R₈ is halogen, NH₂, NO₂, NHC(O)CF₃,NHC(O)CH₃, NHC(NH)NH₂, and the other two radicals are independentlyhydrogen, lower alkyl, lower fluorinated alkyl, benzyl or phenyl;

or a salt or crystal form thereof.

Compounds of formula I may be in the form of a salt preferably apharmaceutically acceptable salt.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of formula I or IV witha basic nitrogen atom, especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,malic acid, tartaric acid, citric acid, amino acids, such as glutamicacid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleicacid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoicacid, oxalic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid,phenylacetic acid, mandelic acid, cinnamic acid, methane- orethane-sulfonic acid, 2-hydroxyethanesulfonic acid,ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonicacid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonicacid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid,N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamicacid, or other organic protonic acids, such as ascorbic acid.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

Preferred salts of formula I, are chloride, bromide, mesylate, acetate,trifluoroacetate.

The term “lower” within the scope of this application denotes radicalshaving up to and including 7, preferably up to and including 4 carbonatoms, preferably methyl or ethyl.

The term “lower fluorinated alkyl” within the scope of this applicationdenotes radicals having up to and including 7, preferably up to andincluding 4 carbon atoms, preferably methyl or ethyl, which aresubstituted by fluorine such as mono, di or trifluoro-methyl,trifluoro-ethyl.

The term “piperazinyl” within the scope of this application denotesunsubstituted piperazinyl or N-lower alkyl-piperazinyl such as4-methyl-piperazinyl-.

Halogen is especially fluorine, chlorine, bromine, or iodine, especiallyfluorine, chlorine, or bromine.

Etherified hydroxy is preferably lower alkoxy. Esterified hydroxy ispreferably hydroxy esterified by an organic carboxylic acid, such as alower alkanoic acid, or a mineral acid, such as a hydrohalic acid, forexample lower alkanoyloxy or especially halogen, such as iodine, bromineor especially fluorine or chlorine.

Alkylated amino is, for example, lower alkylamino, such as methylamino,or di-lower alkylamino, such as dimethylamino. Acylated amino is, forexample, lower alkanoylamino or benzoylamino.

Esterified carboxy is, for example, lower alkoxycarbonyl, such asmethoxycarbonyl.

Preferably, R₃ is lower alkyl substituted by benzylamino, benzoylamino,halogene, pyrrolidinyl, piperidyl, piperazinyl, e.g.4-methyl-piperazinyl-, or morpholinyl, thiomorpholinyl, the substituentsof said substituted radical being selected from the group consisting ofcyano; lower alkyl; hydroxy- or amino-substituted lower alkyl;trifluoromethyl; free, etherified or esterified hydroxy; lower alkoxy;lower alkanoyloxy; free, alkylated or acylated amino; mono- or di-loweralkylamino; lower alkanoylamino; benzoylamino; free or esterifiedcarboxy; lower alkoxycarbonyl and halogen.

Preferably, R₃ is lower alkyl substituted by pyrrolidinyl, piperidyl,piperazinyl, e.g. 4-methyl-piperazinyl-, or morpholinyl,thiomorpholinyl, the substituents of said substituted radical beingselected from the group consisting of lower alkyl; hydroxy- oramino-substituted lower alkyl;

Preferably, R₁, R₂, R₄, R₅ and R₈ are hydrogen.

Preferably, R₇ is lower alkyl such as methyl or fluorinated alkyl suchas trifluoromethyl.

Most preferably, R₃ is (4-methyl-piperazinyl)-methyl, R₁, R₂, R₄, R₅ andR₈ are hydrogen, R₆ is halogen, NH₂, NO₂, NHC(O)CF₃, NHC(O)CH₃,NHC(NH)NH₂, and R₇ is methyl.

Amides of formula I may be prepared by a process as depicted below:

wherein R₁ to R₈ are as defined above and R₉ is hydrogen, methyl, ethylor aryl.

However, direct conversion of unactivated carboxylic acids or esters toamides, such as compounds of formula II, with amines is difficult andtypically requires high reaction temperature, e.g. of about 200° C., oruse of strong bases, such as sodium methoxide, sodium amide, n-butyllithium, sodium hydride or Grignard reagent. Thus there is a need for amore efficient amidation process as hitherto known.

The present Applicants have found that direct conversion of unactivatedcarboxylic acids or esters of compounds of formula II with compounds offormula III to amides of formula I may successfully be conducted undermild conditions

-   A) where R₉ is methyl, ethyl or aryl:    -   in the presence of    -   1) a Lewis acid,    -   2) an aprotic organic solvent, and optionally    -   3) a base,    -   at a temperature of between 20° C. and 80° C., preferably at        about 40° C., for a period of between 1 hour and 1 day,        preferably 8 hours, preferably under inert atmosphere,        preferably at atmospheric pressure, and hydrolysis of the        resulting product; or-   B) where R₉ is hydrogen:    -   in the presence of    -   1) thionylchloride,    -   2) an aprotic organic solvent, and optionally    -   3) a base,    -   at a temperature of between 20° C. and 70° C., preferably 45°        C., for a period of between 1 hour and 1 day, preferably 6        hours, preferably under inert atmosphere, preferably at        atmospheric pressure.

Thus, the present invention provides in another aspect processes for thepreparation of a compound of formula I by reacting compounds of formulaII with compounds of formula III

-   A) where R₉ is methyl, ethyl or aryl:    -   in the presence of    -   1) a Lewis acid,    -   2) an aprotic organic solvent, and optionally    -   3) a base    -   at a temperature of between 20° C. and 80° C., preferably at        about 40° C., for a period of between 1 hour and 1 day,        preferably 8 hours, preferably under inert atmosphere,        preferably at atmospheric pressure, and the resulting product is        hydrolyzed; or-   B) where R₉ is hydrogen:    -   in the presence of    -   1) thionylchloride,    -   2) an aprotic organic solvent, and optionally    -   3) a base,    -   at a temperature of between 20° C. and 70° C., preferably 45°        C., for a period of between 1 hour and 1 day, preferably 6        hours, preferably under inert atmosphere, preferably at        atmospheric pressure.

Suitable Lewis acids for process A) include Al(lower alkyl)₃ (e.g.AlMe₃, AlEt₃, Al(iBu)₃), AlCl₃, AlBr₃, EtAlCl₂, MeAlCl₂, Me₂AlCl,Et₂AlCl and the corresponding sesquichlorides. Preferably, the Lewisacid is selected from AlCl₃, EtAlCl₂ or Et₂AlCl, even more preferably isAlCl₃. Typically, the Lewis acid is present in an amount of 1 to 4 moleequivalents. In the case of AlMe₃, AlEt₃, and Al(iBu)₃, e.g. 2 to 3 moleequivalents, preferably about 2.5 mole equivalents are present; in thecase of AlCl₃, AlBr₃, EtAlCl₂, MeAlCl₂, Me₂AlCl, Et₂AlCl and thecorresponding sesquichlorides, preferably 1.5 to 3.5, preferably 2.5mole equivalents are present.

Thionylchloride is preferably present in process B) in an amount of 1.5to 10 mole equivalents, preferably 1.5 mole equivalents.

Suitable aprotic organic solvents for carrying out process A) and B)include toluene/acetonitrile, toluene, benzene, chlorobenzene,dichlorobenzene, acetonitrile, mesitylene and pyridine.

A preferred base for process A) or B) is N,N-diisopropylethylamine,lutidine, pyridine, or tertiary amines.

In an alternative aspect, the present invention provides a process forthe preparation of compounds of formula I by reacting compounds offormula V with compounds of formula R₁₄—H

wherein,

-   R₁₃ is a lower alkyl substituted by a halogen,-   R₁₄ is benzylamino, benzoylamino, pyrrolidinyl, piperidyl,    piperazinyl, optionally substituted by radicals being selected from    the group consisting of cyano; lower alkyl; hydroxy- or    amino-substituted lower alkyl,-   R₃ is a lower alkyl substituted by benzylamino, benzoylamino,    pyrrolidinyl, piperidyl, piperazinyl, optionally substituted by    radicals being selected from the group consisting of cyano; lower    alkyl; hydroxy- or amino-substituted lower alkyl.

The reaction is preferably carried out in the presence of an organicsolvents, such as THF (Tetrahydrofuran) or directly in the aminesolution R₁₄—H.

Preferably piperazinyl is a N-lower-alkylpiperazine e.g.N-methylpiperazine.

Preferably, R₁, R₂, R₄ and R₅ are independently hydrogen, cyano; loweralkyl; hydroxy- or amino-substituted lower alkyl; trifluoromethyl; free,etherified or esterified hydroxy; lower alkoxy; lower alkanoyloxy; free,alkylated or acylated amino; mono- or di-lower alkylamino; loweralkanoylamino; benzoylamino; free or esterified carboxy; loweralkoxycarbonyl and halogen.

Compounds of formula V can be obtained by reacting compounds of formulaII′ with compounds of formula III,

in the presence of

-   -   1) an organic solvent such as THF (Tetrahydrofuran)    -   2) a base such as N,N-diisopropylethylamine, lutidine, pyridine,        or tertiary amines.

Alternatively, R₁₄—H is directly added in the reactional medium withoutfurther purification in order to react with the resulting compound offormula V.

THF can be used alone or in mixtures with other solvents to increaseoverall solvent power.

The amides of formula I may be formed and isolated from the reactionmixture, e.g. as conventional, e.g. by removal of solvent from thereaction mixture, e.g. by concentration such as evaporation, e.g. todryness or almost dryness, e.g. until crystallization or precipitationof an amide of formula I occurs; or by extraction, e.g. as a salt, orinto another solvent which may be the same or different from that usedin the amidation; and precipitation or crystallization of an amide offormula I. The amides of formula I may be purified by conventionaltechniques such as recrystallization or chromatography.

Compounds of formula II or II′ may be prepared by methods known to theskilled person in the art. Compounds of formula III are commerciallyavailable e.g. from Fluka, Aldrich or Acros or may be prepared bymethods known to the skilled person in the art.

The compounds of formula I may be used for the preparation of compoundsof formula IV,

wherein R₁ to R₅ are as defined above andone of the radicals R₆′, R₇′ and R₈′ is

-   -   wherein R₁₀ is 4-pyperazinyl, 1-methyl-1H-pyrrolyl, amino- or        amino-lower alkyl-substituted phenyl wherein the amino group in        each case is free, alkylated or acylated, 1H-indolyl or        1H-imidazolyl bonded at a five-membered ring carbon atom, or        unsubstituted or lower alkyl-substituted pyridyl bonded at a        ring carbon atom and unsubstituted or substituted at the        nitrogen atom by oxygen, and R₁₁ and R₁₂ are each independently        of the other hydrogen or lower alkyl        and the other two radicals are independently hydrogen, lower        alkyl, e.g. methyl, benzyl or phenyl;        or a pharmaceutically acceptable salt or crystal form thereof.

Compounds of formula IV may be in the form of a salt, preferably apharmaceutically acceptable salt, as described above.

Preferred salts are for example chloride, bromide, mesylate, acetate,trifluoroacetate.

Compounds of formula IV inhibit the tyrosine kinase activity of thereceptor for the epidermal growth factor (EGF) and are useful, interalia, for the treatment of benign or malignant tumors. They are able toeffect tumour regression and to prevent metastatic spread and the growthof micrometastases. In particular, they can be used for treatingepidermal hyperproliferation (psoriasis), for treating neoplasms ofepithelial character, e.g. mastocarcinoma, and leucemia. In addition,the compounds of formula IV are useful for treating diseases of theimmune system and inflammations, subject to the involvement of proteinkinases. The compounds of formula IV may also be used for treatingdiseases of the central or peripheral nervous system, subject to theinvolvement of signal transmission by protein kinases.

Thus, in another aspect the present invention provides a process for thepreparation of compounds of formula IV from compounds of formula I andthe use of compounds of formula I for the preparation of compounds offormula IV wherein R₁ to R₈′ are as herein described.

This invention relates to a process for the preparation of a compound offormula IV or a pharmaceutically acceptable salt or crystal formthereof, by reacting a compound of formula I as described herein, with acompound of formula VII

wherein R₁₀ is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-loweralkyl-substituted phenyl wherein the amino group in each case is free,alkylated or acylated, 1H-indolyl or 1H-imidazolyl bonded at afive-membered ring carbon atom, or unsubstituted or loweralkyl-substituted pyridyl bonded at a ring carbon atom e.g. 3-pyridyland unsubstituted or substituted at the nitrogen atom by oxygen, andR₁₁, and R₁₂ are each independently of the other hydrogen or loweralkyl,

-   -   by conventional methods.

Preferably in a first step, the compound of formula I is prepared fromcompounds of formula II and III as described herein.

The present invention also relates to a process for the preparation of acompound of formula IV or a pharmaceutically acceptable salt or crystalform thereof,

by reacting a compound of formula I as described herein, wherein theradical R₆ is —NHC(NH)NH₂,

with a compound of formula VI

-   -   wherein R₁₀ is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or        amino-lower alkyl-substituted phenyl wherein the amino group in        each case is free, alkylated or acylated, 1H-indolyl or        1H-imidazolyl bonded at a five-membered ring carbon atom, or        unsubstituted or lower alkyl-substituted pyridyl bonded at a        ring carbon atom e.g. 3-pyridyl and unsubstituted or substituted        at the nitrogen atom by oxygen, and R₁₁, is hydrogen or lower        alkyl;        by conventional methods.

Preferably the reaction is carried out in a polar organic solvent suchas n-butanol.

Preferably R₁₀ is 3-pyridyl and R₁₁ is methyl.

In one embodiment, a compound of formula I wherein R₆ is NHC(NH)NH₂, R₇is methyl and R₈ is hydrogen may e.g. be treated with3-dimethylamino-1-(3-pyridyl)-2-propen-1-one to a compound of formula IVwherein R₆′ is 4-(3-pyridyl)-2-pyrimidinamino, R₇′ is methyl and R₈′ ishydrogen, corresponding to the compound of formula IV as described inexample 21 of EP 564 409. A compound of formula I wherein R₆ is Br, R₇is methyl and R₈ is hydrogen may e.g. be treated with4-(3-pyridyl)-2-pyrimidine-amine, e.g. as available from Chempacific, inthe presence of Pd(0) or Pd(II) in the presence of a phosphine ligand togive compound of formula IV wherein R₆′ is4-(3-pyridyl)-2-pyrimidinamino, R₇′ is methyl and R₈′ is hydrogen.

In another embodiment, compounds of formula I wherein R₆ is NO₂, R₇ ismethyl and R₈ is hydrogen may e.g. be transformed to a compound offormula I wherein R₆ is NH₂, R₇ is methyl and R₈ is hydrogen usingstandard methods known to the skilled person. Compounds of formula Iwherein R₆ is halogen, NHC(O)CF₃ or NHC(O)CH₃, preferably Br, R₇ ismethyl and R₈ is hydrogen may e.g. be transformed to a compound whereinR₆ is NH₂, R₇ is methyl and R₈ is hydrogen using standard methods knownto the skilled person. Compounds of formula I wherein R₆ is NH₂, R₇ ismethyl and R₈ is hydrogen may e.g. be transformed to a compound offormula I wherein R₆ is NHC(NH)NH₂, R₇ is methyl and R₈ is hydrogen.

Accordingly, the present invention provides a process for thepreparation of compounds of formula IV wherein in a first step acompound of formula I is prepared from compounds of formula II and IIIas hereinabove described, preferably in the presence of AlCl₃, Al(loweralkyl)₃ e.g. AlMe₃, AlEt₃, Al(iBu)₃ or SOCl₂, and in a second step thecompound of formula I is reacted to a compound of formula IV byconventional methods. Preferably, said process is provided forpreparation of a compound of formula IV wherein R₁, R₂, R₄, R₅ and R₈′are hydrogen, R₃ is (4-methyl-piperazinyl)-methyl, R₆′ is4-(3-pyridyl)-2-pyrimidinamino, and R₇′ is methyl.

The processes of the present invention allow the synthesis of compoundsof formula IV, preferably a compound of formula IV wherein R₁, R₂, R₄,R₅ and R₈′ are hydrogen, R₃ is (4-methyl-piperazinyl)-methyl, R₆′ is4-(3-pyridyl)-2-pyrimidinamino, and R₇′ is methyl, in a more efficientand higher yielding manner than previously described in the literaturee.g. in EP 564409. No expensive coupling reagents have to be used. Thehigher throughput combined with less steps as in the prior art willresult in significantly lower production costs In the previouslydescribed syntheses, mutagenic intermediates may be formed. In theprocesses of the present invention all intermediates show a negativeAMES Test (a specific test for mutagenicity; performed according to theOECD Guideline for Testing of Chemicals, 471: Bacterial Reverse MutationTest, Adopted Jul. 21, 1997) which is a strong indication that nomutagenic intermediates are formed which would be a significantimprovement of occupational health. Furthermore, these processes allowthe synthesis of e.g. radiolabeled compounds.

Following is a description by way of example only of the process of thepresent invention.

AlMe₃ trimethylaluminium from FLUKA Al(iBu)₃ triisobutylaluminium fromFLUKA AlCl₃ aluminium trichloride from Merck platinum on sulfide fromAcros carbon thionyl chloride from FLUKA Celite Filter Cel from FLUKARochelle Salt potassium-sodium tartrate from FLUKA platinum on carbonfrom Engelhardt cyanamide from FLUKA 3-dimethylamino-1- from FLUKApyridin-3-yl-propenone sodium-tert.-butylate from FLUKA rac-BINAP2,2′-bis-(diphenylphos-phino)- 1,1′-binaphthalin synthesized accordingto literature procedure Pd₂(dba)₃*CHCl₃ tris(dibenzylideneacetone)- fromFLUKA dipalladium chloroform complex

Preference is given above all especially to the compound of formula IVwhich isN-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine.N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine(also known as “Imatinib” [International Non-proprietary Name]) and theuse thereof, especially as an anti-tumour agent, are described inExample 21 of European patent application EP-A-0 564 409, which waspublished on 6 Oct. 1993, and in equivalent applications and patents innumerous other countries, e.g. in U.S. Pat. No. 5,521,184 and inJapanese patent 2706682. Another preference is given to the β-crystalform of4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamidemethanesulfonate as described in the European patent application No. 998473 published on May 10, 2000.

The term“4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-yl-amino)phenyl]-benzamide”includes the β-crystal form as described in the European patentapplication No. 998 473.

Very preferably a compound of formula IV is in the form of apharmaceutically acceptable salt, especially in the form of itsmonomesylate salt.

The compounds of formula IV are generically and specifically disclosedin the patent applications EP 0 564 409 A1 and WO 99/03854, inparticular in the compound claims and the final products of the workingexamples, the subject-matter of the final products, the pharmaceuticalpreparations and the claims are hereby incorporated into the presentapplication by reference to these publications. Comprised are likewisethe corresponding stereoisomers as well as the corresponding polymorphs,e.g. crystal modifications, which are disclosed therein.

Thus in a further aspect this invention relates to the use of compoundsof formula I for the synthesis of compounds of formula IV, especially4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamideor a pharmaceutically acceptable salt thereof or crystal form thereof.

Furthermore, this invention also relates to a pharmaceutical compositioncomprising,

-   a) one or more pharmaceutically acceptable excipients,-   b) at least one pharmaceutically active compound of formula IV, and-   c) between 0.00001% and 5% by weight of at least one compound of    formula I, preferably between 0.00001% and 0.1%, most preferably    between 0.0001% and 0.1%.

The present invention particularly relates to pharmaceuticalcompositions especially tablets comprising4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamideor a pharmaceutically acceptable salt or crystal form thereof.

Preferably c) is a compound of formula I wherein, R₃ is(4-methyl-piperazinyl)-methyl, R₁, R₂, R₄, R₅ and R₈ are hydrogen, R₆ isBr, Cl, NH₂, NO₂, NHC(O)CF₃, NHC(O)CH₃ or NHC(NH)NH₂, and R₇ is methyl,or a salt thereof.

One or more pharmaceutically acceptable excipients may be present in thecomposition, e.g. those conventionally used, e.g. (1.1) at least onebinder, e.g. microcrystalline cellulose, hydroxypropylmethyl cellulose,(1.2) at least one disintegrant, e.g. cross-linkedpolyvinylpyrrolidinone, e.g. Crospovidone®, (1.3) at least one glidant,e.g. colloidal silicon dioxide, (1.4) at least one lubricant, e.g.magnesium stearate and/or (1.5) basic coating. In the tablet accordingto the present invention, microcrystalline cellulose is used as abinder.

EXAMPLE A Capsules with Imatinib(4-[(4-methyl-1-piperazin-1-ylmethyl)-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide)methanesulfonate of formula IV, β-crystal form

Capsules containing 119.5 mg of the compound named in the title (=SALTI) corresponding to 100 mg of Imatinib (free base) as active substanceare prepared in the following composition. The composition containingalso compounds of formula I wherein, R₃ is(4-methyl-piperazinyl)-methyl, R₁, R₂, R₄, R₅ and R₈ are hydrogen, R₆ isBr, Cl, NH₂, NO₂, NHC(O)CF₃, NHC(O)CH₃, NHC(NH)NH₂, and R₇ is methyl.

Composition SALT I 119.5 mg Compounds of formula I 0.0005 mg CelluloseMK GR 92 mg Crospovidone XL 15 mg Aerosil 200 2 mg Magnesium stearate1.5 mg 230.0005 mg

The capsules are prepared by mixing the components and filling themixture into hard gelatin capsules, size 1.

EXAMPLE 1 Preparation ofN-(4-Methyl-3-bromo-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide

A solution of trimethylaluminium (2M in toluene, 15.0 ml) is added overa period of 30 min to a solution of 3-bromo-4-methyl-aniline (2.15 g,11.5 mmol) and 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methylester (2.87 g, 11.5 mmol) in toluene (20 ml) at 40° C. under anatmosphere of argon. After gas evolution ceases, the reaction mixture isstirred 30 min before being cooled to 0° C. and partitioned between coldaqueous 1N NaOH (100 ml) and toluene (100 ml). The organic layer isextracted with aqueous saturated NH₄Cl (100 ml) and aqueous saturatedNaCl (100 ml) The organic layer is concentrated in vacuo to give 4.69 g(97 area % by HPLC) of the title compound as pale yellow crystals.

4-(4-Methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester is obtainedas follows:

A solution of 4-formyl-benzoic acid methyl ester (10.0 g, 61 mmol) inmethanol (100 ml) is treated sequentially with 1-methylpiperazine (6.7g, 67 mmol) and platinum (5%) on sulfided carbon (0.5 g). The resultingsolution is then heated at 90° C. and is subjected to a pressure of 5bar of hydrogen for a period of 4 hrs until the hydrogen uptake iscomplete. The reaction mixture is cooled to room temperature andfiltrated over a pad of Celite. The methanol is removed under reducedpressure and replaced with toluene (100 ml). The resulting organicsolution is extracted with aqueous HCl (2N, 2×50 ml). The aqueous layeris treated with concentrated aqueous NaOH (30%) to set the pH to 12 andis back-extracted with toluene (2×50 ml). The combined organic layersare concentrated in vacuo to give 12.9 g (85%) of4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester as a paleyellow oil which may be further purified by distillation under reducedpressure.

EXAMPLE 2A Preparation ofN-(4-Methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide

A solution of trimethylaluminium (2M in toluene, 1.3 ml, 2.6 mmol) isadded over a period of 5 min to a solution of3-nitro-4-methyl-aniline(152 mg, 1.00 mmol) and4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (248 mg,1.00 mmol) in toluene (3.0 ml) at 45° C. under an atmosphere of argon.After gas evolution ceases, the dark brown reaction mixture is stirred30 min before being cooled to 0° C. An aqueous saturated solution ofpotassium-sodium tartrate (20 ml), t-butyl methyl ether (15 ml) andmethylene chloride (10 ml) are added sequentially. The organic phase isseparated and washed with aqueous saturated NaHCO₃ (10 ml) and aqueoussaturated NaCl (10 ml). The aqueous phases are back-extracted witht-butyl methyl ether (2×15 ml). The organic phases are combined, driedover MgSO₄ and concentrated in vacuo to give 383 mg (96 area % by HPLC)of the title compound as pale yellow crystals.

EXAMPLE 2B Preparation ofN-(4-Methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide

To a solution of 10.95 g (72 mmol) of 3-nitro-4-methyl-aniline in 80 mlof toluene is added a solution of triisobutylaluminium (28% in hexane),66.5 ml (61 mmol) over a period of 30 min at 0° C. followed by theaddition of a solution of, 4-(4-methyl-piperazin-1-ylmethyl)-benzoicacid methyl ester (14.9 g, 60 mmol) in toluene (30 ml) during 1 hour at0° C. under an atmosphere of argon. After stirring for 12 h at roomtemperature an other portion of triisobutylaluminium (66.5 ml (61 mmol)is added to the dark brown reaction mixture. The mixture is stirred foradditional 6 h, then 2 additional small portions of triisobutylaluminium(each 18 ml, 18 mmol) are added and stirring is continued for severalhours at room temperature. After acidic and basic workup with sulfuricacid and NaOH the combined organic toluene phases are evaporated invacuo to give a brown crude product which was crystallized from t-butylmethyl ether to give the title compound as brownish yellow crystals:first crop (11.65 g), sec. crop (3.8 g) and a third crop (1.2 g). insummary 16.65 g (75.3%).

EXAMPLE 2C Preparation ofN-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide

4-methyl-3-nitroaniline (30.0 g, 0.197 mol) is added to a mixture oftetrahydrofuran (120 ml) and N-ethyl-N,N-diisopropyl-amine at 23-25° C.over a period of 5 to 10 min. To this solutionchloromethyl-benzoylchloride (38.4 g, 0.20 mol) dissolved intetrahydrofuran (35 ml) is added over a period of 60-65 min maintaininga temperature of 25-30° C. The reaction mixture is stirred at thistemperature for 30 min and then added to N-methylpiperazine (138.2 g,1.38 mol) over a period of 60 to 90° C. maintaining a temperature of25-30° C. The resulting suspension is stirred at this temperature for 60min. Tetrahydrofurane is distilled of at 50° C. under reduced pressure.At the end of the distillation the temperature is adjusted to 45-48° C.and water (300 ml) is added over a period of 45-60 min at thistemperature. The resulting suspension is cooled to 23° C. and stirredfor 60 min. The suspension is filtered, the filtercake washed with water(225 ml) and dried in vacuo to give 69.2 g of the title compound (95% oftheory) as an of-white powder (99.5% area by HPLC).

Alternatively the intermediateN-(4-methyl-3-nitro-phenyl)-4-chloromethyl-benzamide can be isolated bydistilling of half of the tetrahydrofuran under reduced pressure andadding the residue to water (300 ml) at a temperature of 20-25° C. overa period of 30 min. After stirring for another 30 min at 0-5° C., thesuspension is filtered, washed with water (200 ml) and dried in vacuo.The intermediate is dissolved in tetrahydrofuran (150 ml) and added toN-methylpiperazine (138.2 g, 1.38 mol) over a period of 60 to 90 minmaintaining a temperature of 25-30° C. The title compound can beisolated following the above described procedure.

EXAMPLE 3 Preparation ofN-(4-Methyl-3-trifluoroacetimidate-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide

A solution of trimethylaluminium (2M in toluene, 1.25 ml, 2.5 mmol) isadded over a period of 5 min to a solution of3-trifluoroacetimidate-4-methyl-aniline (218 mg, 1.00 mmol) and4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (248 mg,1.00 mmol) in toluene (3.0 ml) at 0° C. under an atmosphere of argon.After gas evolution ceases, the dark brown reaction mixture is stirred 3hrs at 23° C. before being cooled to 0° C. An aqueous saturated solutionof potassium-sodium tartrate (20 ml) and t-butyl methyl ether (40 ml)are added sequentially. The organic phase is separated and washed withaqueous saturated NaHCO₃ (20 ml) and aqueous saturated NaCl (20 ml). Theaqueous phases are back-extracted with t-butyl methyl ether (2×20 ml).The organic phases are combined, dried over MgSO₄ and concentrated invacuo to give 458 mg (94 area % by HPLC) of the title compound as whitecrystals.

EXAMPLE 4 Preparation ofN-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide

A solution of AlCl₃ (1000 mg, 7.5 mmol) in toluene (3 ml) andacetonitrile (3.0 ml) at 0° C. under an atmosphere of argon is treateddropwise with a solution of 3-amino-4-methyl-aniline (470 mg, 6.0 mmol)in toluene (6 ml). The resulting brown solution is heated at 40° C. Asolution of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester(745 mg, 3.0 mmol) in toluene (2 ml) is then added dropwise over aperiod of 30 min. The resulting mixture is stirred at 40° C. for 8 hrsand then cooled at 0° C. An aqueous saturated potassium-sodium tartrate(30 ml) and aqueous saturated NaHCO₃ (40 ml) and t-butyl methyl ether(60 ml) are added sequentially. The organic phase is separated andwashed with aqueous saturated NaCl. The aqueous phases areback-extracted with t-butyl methyl ether. The organic phases arecombined, dried over MgSO₄ and concentrated in vacuo. Purification byflash-chromatography (SiO₂, CH₂Cl₂/MeOH 90:10+1% aq. NH₃) gives 825 mgof the title compound (75%) as yellowish crystals.

EXAMPLE 5 Preparation ofN-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide

Thionyl chloride (53.3 g, 448 mmol) is added over a period of 15 min toa suspension of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (70.0 g,299 mmol) in toluene (300 ml) at 0° C. At the end of the addition, thereaction mixture is heated at 23° C. over a period of 45 min. The excessof SOCl₂ is removed by co-distillation with toluene under reducedpressure at 40° C. At the end of the distillation, the resultingsuspension id cooled down to 0° C. and the benzoyl chloride is filteredoff, washed with toluene (2×50 ml) and dried in vacuo at 45° C.overnight.

Yield: 55.0 g, 79% of theory based on the di-hydrochloride salt of thebenzoylchloride, white solid. The dried benzoyl chloride (55 g) is thenresuspended in toluene (100 ml). A solution of 4-methyl-3-nitroaniline(22.75 g, 145 mmol) and pyridine (34.4 g, 435 mmol) in toluene (60 ml)is added dropwise at 23° C. over a period of 15 min. The resultingorange-brown reaction mixture is heated at 45° C. and is stirred for 6hrs. The suspension is filtrated and the filtercake is washedsuccessively with toluene (300 ml) and acetone (350 ml), and is thensuspended in water (350 ml). Aqueous NaOH (30%) is added until the pH ofthe suspension reaches 11 and remains stable. The suspension is furtherstirred for 1 h at 40° C. before being filtrated. The filtercake iswashed with water (5×50 ml) and dried in vacuo to give 51.3 g of thetitle compound (96%) as beige crystals, (98.7% area by HPLC).

Preparation of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid

A suspension of 4-formyl-benzoic acid (10.0 g, 67 mmol) in methanol (100ml) is treated sequentially with 1-methylpiperazine (7.3 g, 73 mmol) andplatinum (5%) on sulfided carbon (1 g). The resulting suspension is thenheated at 80° C. and is subjected to a pressure of 5 bar of hydrogen fora period of 20 hrs until the hydrogen uptake is complete. The reactionmixture is cooled to room temperature and filtrated over a pad ofCelite. Water (20 ml) is used to rinse the reactor and dissolve thefraction of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid thatcrystallizes on the walls during the cooling of the reaction mixture.The resulting aqueous solution is filtrated over the pad of Celiteemployed previously. The combined filtrates are concentrated in vacuoand crystallized in EtOH/H₂O 9:1 v/v to give 10.9 g (70%) of4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid as colorless crystals.

EXAMPLE 6 Preparation ofN-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benz-amide

In analogous manner to Example 4, 3-guanidino-4-methyl-aniline (2.51 g,11.5 mmol).and 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (70.0 g,299 mmol) in toluene (300 ml) in the presence of thionyl chloride (53.3g, 448 mmol) give 12.1 g (89%) of the title compound as pale colorlesscrystals.

EXAMPLE 7 Preparation of4-dichloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide

To a suspension of4-methyl-N*3*-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine (2.00g mg, 7.21 mmol) in toluene (22 ml) at 45° C. under an atmosphere ofargon is added sequentially 4-dichloromethyl-benzoic acid methyl ester(1.90 g, 8.67 mmol) and AlMe₃ (2 M in toluene, 12.6 ml, 25.2 mmol). Theresulting brown solution is stirred at 45° C. for a period of 3.5 hrs.The reaction mixture is then cooled to 0° C. and quenched by slowaddition of a saturated aqueous solution of Rochelle salt (70 ml) whichcauses the precipitation of the crude product. t-Butyl methyl ether (150ml) and methylene chloride (100 ml) are added sequentially to thesuspension which are then washed with aqueous saturated NaHCO₃ (100 ml)and aqueous saturated NaCl (100 ml). The aqueous phases areback-extracted with t-butyl methyl ether (100 ml). The crude product,which is contained in the combined organic phases, is filtered off withsuction, washed with t-butyl methyl ether and dried in vacuo. Yield:3.35 g of the title compound, 84% of theory, as beige crystals, (HPLC:91% area).

EXAMPLE 8 Preparation ofN-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benz-amide

In analogous manner to Example 4, 3-guanidino-4-methyl-aniline (1.00 g,6.09 mmol) and 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methylester (1.50 g, 6.04 mmol) in toluene (22 ml) and acetonitrile (6 ml) inthe presence of AlCl₃ (2.0 g, 15.0 mmol) at 40° C. give 1.26 g (55%) ofthe title compound as pale colorless crystals.

EXAMPLE 9 Preparation of4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide

A suspension ofN-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benz-amide(30 g, 79 mmol) in n-butanol (150 ml) at 120° C. under an atmosphere ofnitrogen is treated with 3-dimethylamino-1-pyridin-3-yl-propenone (15.3g, 87 mmol). The resulting suspension is heated at 150° C. for 5 hrs.The reaction mixtures becomes a homogeneous deep orange solution anddimethylamine is removed by the distillation of n-butanol (130 ml).n-Butanol (20 ml) is added during the distillation. Butyl acetate (60ml) is added dropwise at 100° C. and the solution is cooled to 0° C.within 1 hr and stirred at 0° C. for 16 hrs. The resulting deep orangesuspension is filtered off with suction, the isolated solid is washedwith n-butanol (2×50 ml) and water (2×50 ml) and dried in vacuo at 60°C. Yield: 36.4 g of the title compound, 93% based on theory, asoff-white crystals. (99.6% area by HPLC).

EXAMPLE 10 Preparation of4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide

To a mixture of 4-(3-pyridyl)-2-pyrimidine-amine (172.2 mg, 1.0 mmol),N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide(402.4 mg, 1.0 mmol) and sodium tert.-butylate (144.2 mg, 1.5 mmol) isadded a mixture of rac-BINAP (31.2 mg, 0.050 mmol) and Pd₂(dba)₃*CHCl₃(13 mg, 0.013 mmol) under argon. After addition of 3 ml of xylene thesuspension is sonicated for 10 minutes then stirred for 5 hours underreflux. After cooling to room temperature, water (10 ml) is added to thedark brown oil and the product extracted 4 times with methylene chloride(10 ml each). The combined organic extracts are dried over MgSO₄ andconcentrated in vacuo. The brown oil is purified by flash-chromatography(SiO₂, methanol). The product, a pale yellow solid is dissolved inmethylene chloride, filtered and concentrated in vacuo. Yield: 484.3 mgof the title compound, 72% of theory, (99.9% area by HPLC). The productcontains typically roughly 10% of isomers which can be eliminated bypreparative reversed phase chromatography.

EXAMPLE 11 Preparation ofN-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide

A solution ofN-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide(100 g, 260 mmol) in n-butanol (1 l) is treated with platinum (5%) oncarbon (1.0 g). The resulting suspension is then heated to 70° C. andhydrogen is applied with a pressure of 0.2 bar for a period of 6 h untilthe hydrogen uptake is complete. The reaction mixture is cooled to roomtemperature and filtrated. n-Butanol is used to wash the catalyst. Thissolution is suitable for example 12. For isolation of the product isreduced to a third and crystallized by cooling down to 0° C. (HPLC:98.0% area).

Alternatively a solution ofN-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide(60 g, 163 mmol) in ethanol 90% (300 ml) at room temperature under anatmosphere of nitrogen is treated sequentially with platinum (5%) oncarbon (6.0 g) and potassium formate (68.5 g, 814 mmol). The resultingsuspension is then heated at 80° C. for a period of 16 hrs. The reactionmixture is filtrated at 70° C. over a pad of Celite. Ethanol 90% (150ml) and water (150 ml) are used to rinse the reactor. Ethanol is removedfrom the combined filtrates by distillation in vacuo at an externaltemperature 60° C. The crude product separates from the aqueousconcentrate as an oil during the distillation, crystallizes uponsubsequent cooling to 23° C. within 2 hrs and is filtered of withsuction, washed with ethanol (200 ml) and dried in vacuo. Yield: 55 g ofthe title compound, 99% of theory, as yellowish crystals. (HPLC: 98.0%area).

EXAMPLE 12 Preparation ofN-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benz-amide

A suspension ofN-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide(50 g, 144 mmol) in n-butanol (300 ml) at 85° C. is treated sequentiallywith concentrated aqueous HCl until the pH reaches 2.5 (HCl 37%, 35 g)and with a solution of cyanamide (12.1 g, 288 mmol) in water (12 ml)over a period of 30 min. The resulting reaction mixture is stirred at85° C. for 20 hrs during which time the starting material dissolves andthe desired product crystallizes out of solution as the di-hydrochloridesalt. Concentrated HCl (37%, 6.3 g) is added during the reaction tomaintain the pH at 2.5. The reaction mixture is then allowed to cooldown to room temperature within 1.5 hrs. The product is filtered offwith suction, washed with n-butanol (3×50 ml) and dried in vacuo at 60°C. Yield 60.7 g of the di-hydrochloride salt, 93% of theory (99% area byHPLC).

The di-hydrochloride salt is dissolved in water (250 ml) at 35° C. Anaqueous solution of NaOH (2N, 150 ml) is added and the pH of thesolution increases to 13.2. The desired product separates from theaqueous solution as an oil which crystallizes upon cooling to 0° C.After 1 hr stirring at 0° C., the product is filtered off, washed withan aqueous solution of K₂CO₃ (5.5 g/L, 2×50 ml) and dried in vacuo at50° C. Yield: 41.2 g of the title compound, 89% of theory based on theintermediate di-hydrochloride salt, as beige crystals, (98.7% area byHPLC).

1. Process for the preparation of a compound of formula I

wherein R₃ is (4-methyl-piperazinyl)-methyl and R₁, R₂, R₄ and R₅ areindependently hydrogen, cyano; lower alkyl; hydroxy- oramino-substituted lower alkyl; trifluoromethyl; hydroxy, etherified oresterified hydroxy; lower alkoxy; lower alkanoyloxy; amino, alkylated oracylated amino; mono- or di-lower alkylamino; lower alkanoylamino;benzoylamino; carboxy or esterified carboxy; lower alkoxycarbonyl andhalogen; R₆ is halogen, NH₂, NO₂, NHC(O)CF₃, NHC(O)CH₃, or NHC(NH)NH₂,R₇ is methyl and R₈ is hydrogen; or a salt or crystal form thereof,wherein a compound of formula II

is reacted with an amine of formula III

A) wherein R₉=methyl, ethyl or aryl: in the presence of 1) a Lewis acidselected from Al(lower alkyl)₃, AlCl₃, EtAlCl₂, MeAlCl₂, Me₂AlCl,Et₂AlCl or the corresponding sesquichlorides, 2) an organic solvent, andoptionally 3) a base, and the resulting product is hydrolyzed; or B)wherein R₉=hydrogen: in the presence of 1) thionylchloride, 2) anorganic solvent, and optionally 3) a base.
 2. A process according toclaim 1 wherein the Lewis acid in A) is selected from AlMe₃, AlEt₃,Al/Bu₃, AlCl₃, EtAlCl₂ and Et₂AlCl.
 3. A process according to claim 1wherein the process is carried out at a temperature of 20° C. to 80° C.4. A process for the preparation of a compound of formula IV

wherein R₃ is (4-methyl-piperazinyl)-methyl and R₁, R₂, R₄ and R₅ areindependently hydrogen, cyano; lower alkyl; hydroxy- oramnino-substituted lower alkyl; trifluoromethyl; hydroxy, etherified oresterified hydroxy; lower alkoxy; lower alkanoyloxy; amino, alkylated oracylated amino; mono- or di-lower alkylamino; lower alkanoylamino;benzoylamino; carboxy or esterified carboxy; lower alkoxycarbonyl andhalogen; one of the radicals R₆′, R₇′ and R₈′ is

wherein R₁₀ is 4-pyperazinyl, 1-methyl-1H-pyrrolyl, amino- oramino-lower alkyl-substituted phenyl wherein the amino group in eachcase is free, alkylated or acylated, 1H-indolyl or 1H-imidazolyl bondedat a five-membered ring carbon atom, or unsubstituted or loweralkyl-substituted pyridyl bonded at a ring carbon atom and unsubstitutedor substituted at the nitrogen atom by oxygen, and R₁₁ and R₁₂ are eachindependently of the other hydrogen or lower alkyl and the other tworadicals are independently hydrogen, lower alkyl, benzyl or phenyl; or apharmaceutically acceptable salt or crystal form thereof, whichcomprises preparing a compound of the formula I

wherein R₁, R₂, R₃, R_(4,) and R₅ are defined above, R₆ is halogen, NH₂,NO₂, NHC(O)CF₃, NHC(O)CH₃, or NHC(NH)NH₂, R₇ is methyl, and R₈ ishydrogen; or a salt or crystal form thereof, wherein a compound offormula II

is reacted with an amine of formula III

A) wherein R₉=methyl, ethyl or aryl: in the presence of 1) a Lewis acidselected from Al(lower alkyl )₃, AlCl₃, EtAlCl₂, MeAlCl₂, Me₂AlCl,Et₂AlCl or the corresponding sesquichlorides, 2) an organic solvent, andoptionally 3) a base, and the resulting product is hydrolyzed; or B)wherein R₉=hydrogen: in the presence of 1) thionylchloride, 2) anorganic solvent, and optionally 3) a base.
 5. Process according to claim4 for the preparation of a compound of formula IV wherein R₁, R₂, R₄, R₅and R₈′ are hydrogen, R₃ is (4-methyl-piperazinyl)-methyl, R₆′ is4-(3-pyridyl)-2-pyrimidinamino, and R₇′ is methyl, or a pharmaceuticallyacceptable salt or crystal form thereof.